CN1050130C - Naloxonate and naltrexonate and series product and preparation method - Google Patents
Naloxonate and naltrexonate and series product and preparation method Download PDFInfo
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- CN1050130C CN1050130C CN97112842A CN97112842A CN1050130C CN 1050130 C CN1050130 C CN 1050130C CN 97112842 A CN97112842 A CN 97112842A CN 97112842 A CN97112842 A CN 97112842A CN 1050130 C CN1050130 C CN 1050130C
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- naltrexone
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- naloxone
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Abstract
The present invention relates to Na-loxne acid ester and Naltrexone acid ester and a preparation method thereof. Na-loxne, Naltrexone, phenolic hydroxyl in the third position, alcohol hydroxyl in the fourteenth position, carboxylic acid and derivatives thereof carry out esterification reaction at the temperature of 80 to 125 DEG C, and then, the Na-loxne acid ester and Naltrexone acid ester are prepared. The Na-loxne acid ester and the Naltrexone acid ester and the series product thereof do not change the antagonistic action of the Na-loxne and the Naltrexone, extend the action time in human bodies, are suitable for the clinical requirements, and enlarge the application prospect in clinic.
Description
The present invention relates to pharmaceutical chemical substance technical field, specifically naloxonate and naltrexonate and series matter and preparation method.
Naloxone of the prior art (Naloxoe), its chemical structure are 17-(2-allyl group)-4,5a-epoxy-3, the two hydroxyl morphinanes of 14--6-ketone.Itself no tolerance and habituation is the exclusive antagonist of a kind of opiate receptor, and it can all block combining of morphine and opiate receptor, (0.4mg) intramuscular injection of clinical low dose or quiet notes can overturn the rapidly analgesia and the respiration inhibition effect of morphine class material.Therefore, this product is mainly used in the acute poisoning of treatment morphine class medicine (as: heroine etc.) and the instrument medicine that screens as anodyne.Clinical study this product in recent years also can be used for sick treatment such as schizophrenia, cerebral infarction, senile dementia, antishock, ethylism, obesity, congenital absence of pain, baby's asphyctic syndrome, habitual constipation, is found in No. 081, " old medicine is newly used " (capital) Xindeng word.The transformation period is 90 minutes in its human body of existing naloxone hydrochloride, acting on working lipe is 4 hours, because it is too short intravital action time the people, oral drug effect is low only to be 1/50 of drug administration by injection, necessary again intramuscular injection or quiet notes, can not get a desired effect far away, in the treatment of chronic disease, only limit to scientific research, be difficult to promote.
Naltrexone (Naltrexone), its chemical structure are that 17-encircles third methyl-4,5a-epoxy-3, the two hydroxyl morphinanes of 14--6-ketone.Itself no tolerance and habituation is pure opioid antagonist, and this material can all be blocked the pharmacology usefulness of intravenous injection opioid (as: heroine etc.) by the competitiveness combination at the opiate receptor position.And naltrexone can make the interior Opioid Receptor System hypersensitization of patient's body or raise, and eliminates chronic withdrawal symptom thereby alleviate, and reduces relapse rate.Thereby after the naltrexone person's detoxification that is the opiate addiction, domestic and foreign current consolidate curative effect, anti-unique medicine of reverting to take drugs, make the addict really go on the road of physiology, psychological rehabilitation.But, need the decubation of half a year to two year because of individual difference.The existing intravital transformation period of its people of hydrochloric acid naltrexone is 12.9 hours, acting on working lipe is 72 hours, because naltrexone is too short action time in human body, though can block opiates effectively, but decubation needs complying with of patient and cooperates, the patient of compliance difference takes off the mistake phenomenon easily in drug administration process, cause the treatment failure.Take naltrexone once more, need to bring difficulty to clinical application through using after the detoxification once more.
The objective of the invention is to address the above problem, a kind of naloxonate and naltrexonate and series matter and preparation method with antagonistic action that long-acting keeps naloxone and naltrexone again is provided.
Its structural formula of naloxone acid esters of the present invention and naltrexone acid esters is:
R in the formula
1Represent the 2-allyl group, or encircle third methyl.
R in the formula
2, R
3Represent hydrogen atom, or straight or branched (C
1～C
15) alkyl, or this alkyl group is unsubstituted or by one or more phenyl ring or encircle penta ring and replace.
R in the naloxone acid esters
1Represent the 2-allyl group, but its series matter naloxone capronate, naloxone heptanoate, naloxone octanoate, naloxone pelargonate, naloxone decylate, naloxone undecylate, naloxone cetylate, benzoate, toluylic acid fat, phenylpropionic acid fat, cyclopentyl propionic acid fat.
R in the naltrexone acid esters
1Representative ring third methyl, but its series matter naltrexone capronate, naltrexone heptanoate, naltrexone octanoate, naltrexone pelargonate, naltrexone decylate, naltrexone undecylate, naltrexone cetylate, benzoate, toluylic acid fat, phenylpropionic acid fat, cyclopentyl propionic acid fat.
The preparation method of above-mentioned substance generates naloxone acid esters, naltrexone acid esters with naloxone, naltrexone and carboxylic acid and derivative thereof through esterification.Specifically naloxone, naltrexone be under 80-125 ℃ temperature control, goes up phenolic hydroxyl group, 14 for its 3 and go up alcoholic extract hydroxyl group and carboxylic acid and derivative acid anhydrides thereof, acyl fontanel, acid amides, ester etc. and react and generate.Its reaction formula is:
R=R in the formula
2=R
3And R
1Definition same as above.
X represents fontanelle atom in the formula, or hydroxyl, or amino.
The starting compound naloxone can be bought, and perhaps the manufacture method according to " thing is made encyclopedia " the 607th page is prepared by the professional and technical personnel.The starting compound naltrexone can be bought, and perhaps according to the synthetic route in the following document, is prepared by the professional and technical personnel.
U.S.P，3332950(1967)
CA.67：10030a
J.Med.Chem，1984，49：2081
Raw material carboxylic acid and derivative thereof can be by " whole nation material pharmaceutical worker plant compilation ", " pharmaceuticals production technique compilations ", " organic drug becomes handbook, and it is standby to prepare a series of carboxylic acid derivative by the professional technician.For example: palmityl chloride, palmitic amide, undecanoyl chlorine, undecanoic amide, decyl amide, decanoyl chloride, oenanthyl chloro, heptylic anhydride, encircle penta propionyl chloride, β-cyclopentyl propionic acid acid anhydride, phenylpropionic acid acyl chlorides, benzene second, phenylformic acid acyl chlorides.
A series of naloxone carboxylate of the present invention and naltrexone carboxylate do not change the antagonistic action of naloxone and naltrexone, and have prolonged the intravital action time the people.Adapt to clinical demand, enlarged potential applicability in clinical practice.Naloxonate weekly or the first quarter moon medication once just can make the mental patient's of oneself no cognitive ability the state of an illness is greatly taken on a new look, its systematic treating has been had guarantee.Naltrexonate first quarter moon or medication in January have once made things convenient for the supervision to the medication people to help, and the change route of administration is tired and improved 4 times, reduces patient's ability to shoulder economically, is easier to promote.
The invention will be further described below in conjunction with embodiment:
Embodiment 1:
Accurately the pure product 0.5 of weighing naloxone restrain, and heating is dissolved in 1.25 ml distilled waters, adds toluene and extracts for 1.5 milliliters, gets toluene layer and puts into retort, is heated to backflow.Gradation drips 0.34 milliliter of decanoyl chloride, continues to reflux 16 hours.Be chilled to room temperature,, wash with water to neutrality with 6% sodium hydroxide solution and the washing of 5% sodium carbonate solution.Get crude product behind the reclaim under reduced pressure toluene.With the water dissolution crude product of 5 times of amounts, adding 30% liquid caustic soda to pH value is 11, extracts with the chloroform gradation of 4 times of amounts, and united extraction liquid is washed to neutrality, leaves standstill branchs and gets chloroform layer, after normal pressure reclaims chloroform, naloxone decylate 0.376 restrain fusing point 58-60 ℃.
Embodiment 2:
Accurately pure product 0.5 gram of weighing naloxone adds 0.5 milliliter of 1.5 milliliters of toluene and a-picoline, stirs, and heats to 80-90 ℃, and gradation drips 0.45 milliliter of palmityl chloride, continues to stir 48 hours.Inject 6 times of water gagings while hot, stirred ten minutes, leave standstill branch and get toluene layer, add 10 times of amount 95% ethanol in the toluene layer and reach the solution of the MALEIC ANHYDRIDE that is mixed with by 6.5 times of amount ethanol and an amount of gac, add heat decoloring, filtered while hot, the filtrate cooling is filtered.Filter cake filters with 60 ℃ sodium bicarbonate water washing.Filter cake is poured in 15 times of water gagings, separates out crude product and removes the liquid that anhydrates, and washes with water to the non-pyridine flavor, filters.Filter cake adds 5 times of water gagings, and adding 30% liquid caustic soda to pH value is 11, extracts with the ether gradation of 4 times of amounts, and united extraction liquid is washed to neutrality, leaves standstill branchs and gets ether layer, after normal pressure reclaims ether, naloxone cetylate 0.365 restrain fusing point 61-62 ℃.
Embodiment 3:
Accurately the pure product 0.5 of weighing naltrexone restrain, and heating is dissolved in 1.25 ml distilled waters, adds toluene and extracts for 1.5 milliliters, gets toluene layer and puts into retort, is heated to backflow.Gradation drips 0.325 milliliter of decanoyl chloride, continues to reflux 16 hours.Be chilled to room temperature,, wash with water to neutrality with 6% sodium hydroxide solution and the washing of 5% sodium carbonate solution.Get crude product behind the reclaim under reduced pressure toluene.With the water dissolution crude product of 5 times of amounts, adding 40% liquid caustic soda to pH value is 11, extracts with the chloroform gradation of 4 times of amounts, and united extraction liquid is washed to neutrality, leaves standstill branchs and gets chloroform layer, after normal pressure reclaims chloroform, naltrexone decylate 0.421 restrain fusing point 58-60 ℃.
Embodiment 4:
Accurately pure product 0.5 gram of weighing naltrexone adds 0.5 milliliter of 1.5 milliliters of toluene and a-picoline, stirs, and heats to 80-90 ℃, and gradation drips 0.443 milliliter of palmityl chloride, continues to stir 48 hours.Inject 6 times of water gagings while hot, stirred ten minutes, leave standstill branch and get toluene layer, add 10 times of amount 95% ethanol in the toluene layer and reach the solution of the MALEIC ANHYDRIDE that is mixed with by 6.5 times of amount ethanol and an amount of gac, add heat decoloring, filtered while hot, the filtrate cooling is filtered.Filter cake filters with 60 ℃ sodium bicarbonate water washing.Filter cake is poured in 15 times of water gagings, separates out crude product and removes the liquid that anhydrates, and washes with water to the non-pyridine flavor, filters.Filter cake adds 5 times of water gagings, and adding 40% liquid caustic soda to pH value is 11, extracts with the ether gradation of 4 times of amounts, and united extraction liquid is washed to neutrality, leaves standstill branchs and gets ether layer, after normal pressure reclaims ether, naltrexone cetylate 0.388 restrain fusing point 62-63 ℃.
Embodiment 5: get 20 milliliters of oils for injection and be heated to 150 ℃, be incubated 1.5 hours, put be chilled to 40 ℃ after, get 100 milliliters of oils for injection and add 300 milliliters of phenylcarbinols, stir, add 400 milligrams of naloxone palmitic acid lipids again, be stirred well to molten (solvent temperature is controlled at 40-45 ℃), and another 100 milliliters of oils for injection are added, be that 2% naloxone palmitinic acid fatty oil absorbs and penetrates liquid this moment.Be sub-packed in 1 milliliter of small jar with dry G3 acid funnel filtration, adorn 1.1 milliliters for every, fill the nitrogen sealing by fusing and promptly get 1 milliliter every naloxone palmitic acid lipid injection liquid that contains 20 milligrams, then 100 ℃ of sterilizations in 30 minutes are standby.
Claims (6)
1, a kind of naloxonate or naltrexonate is characterized in that the structural formula of naloxone acid esters or naltrexone acid esters is:
R in the formula
1Represent the 2-allyl group, or encircle third methyl,
R in the formula
2, R
3Represent hydrogen atom, or straight or branched (C
1～C
15) alkyl, this alkyl is unsubstituted or by one or more phenyl ring or encircle penta ring and replace.
2, by the described naloxonate of claim 1, it is characterized in that the R in the naloxone acid esters
1Represent the 2-allyl group, but its series matter naloxone capronate, naloxone heptanoate, naloxone octanoate, naloxone pelargonate, naloxone decylate, naloxone undecylate, naloxone cetylate, benzoate, toluylic acid fat, phenylpropionic acid fat, cyclopentyl propionic acid fat.
3, by the described naltrexonate of claim 1, it is characterized in that the R in the naltrexone acid esters
1Representative ring third methyl, but its series matter naltrexone capronate, naltrexone heptanoate, naltrexone octanoate, naltrexone pelargonate, naltrexone decylate, naltrexone undecylate, naltrexone cetylate, benzoate, toluylic acid fat, phenylpropionic acid fat, cyclopentyl propionic acid fat.
4, the preparation method of the naloxonate of claim 1 and naltrexonate, it is characterized in that going up phenolic hydroxyl groups, 14 by 3 of naloxones (Naloxne), naltrexone (Naltrexone) goes up alcoholic extract hydroxyl group and carboxylic acid and derivative thereof and generate through esterification, can be described by following reaction formula under 80-125 ℃ of temperature:
R=R in the formula
2=R
3And R
1Definition with claim 1;
X represents fontanelle atom in the formula, or hydroxyl, or amino.
5, by the described preparation method of claim 4, it is characterized in that carboxylic acid and derivative thereof are by containing C
1～C
16A series of derivatives such as the acyl fontanel that forms of carboxylic acid, acid anhydrides, acid amides, ester, particularly palmityl chloride, palmitic amide, undecanoyl chlorine, undecanoic amide, decanoyl chloride, decyl amide, heptylic anhydride, oenanthyl chloro, ring penta propionyl chloride, β-cyclopentyl propionic acid acid anhydride, the phenylpropionic acid acyl chlorides, benzene second, phenylformic acid acyl chlorides.
6, a kind of pharmaceutical composition is characterized in that containing each compound in the claim 1,2,3, combines with any appropriate excipients simultaneously.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97112842A CN1050130C (en) | 1997-07-04 | 1997-07-04 | Naloxonate and naltrexonate and series product and preparation method |
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|---|---|---|---|
| CN97112842A CN1050130C (en) | 1997-07-04 | 1997-07-04 | Naloxonate and naltrexonate and series product and preparation method |
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| Publication Number | Publication Date |
|---|---|
| CN1204649A CN1204649A (en) | 1999-01-13 |
| CN1050130C true CN1050130C (en) | 2000-03-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97112842A Expired - Fee Related CN1050130C (en) | 1997-07-04 | 1997-07-04 | Naloxonate and naltrexonate and series product and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9969746B2 (en) | 2013-12-05 | 2018-05-15 | The University Of Bath | Opioid compounds and their uses |
| WO2022091131A1 (en) * | 2020-10-27 | 2022-05-05 | Navin Saxena Research & Technology Pvt. Ltd. | Process for preparation of pure naltrexone decanoate, its salts, composition and method of use thereof |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333798C (en) * | 2005-11-10 | 2007-08-29 | 昆明依利科特科技有限公司 | Naloxone eye drops |
| CN106317064B (en) * | 2015-06-30 | 2018-06-19 | 北大方正集团有限公司 | The preparation method of methylnaltrexone bromide |
| AU2018359336B2 (en) * | 2017-11-03 | 2024-06-20 | Nirsum Laboratories, Inc. | Opioid receptor antagonist prodrugs |
| CA3091826A1 (en) | 2018-02-23 | 2019-08-29 | Rhodes Technologies | Novel opioid compounds and uses thereof |
| WO2020012245A1 (en) | 2018-07-13 | 2020-01-16 | Alkermes Pharma Ireland Limited | Thienothiophene-naltrexone prodrugs for long-acting injectable compositions |
| WO2020012248A1 (en) | 2018-07-13 | 2020-01-16 | Alkermes Pharma Ireland Limited | Novel naphthylenyl compounds for long-acting injectable compositions and related methods |
| US11186585B2 (en) | 2018-08-17 | 2021-11-30 | Kappa-Pharma LLC | Compositions and methods of enhancing opioid receptor engagement by opioid hexadienoates and optionally substituted hexadienoates |
| WO2020094634A1 (en) | 2018-11-05 | 2020-05-14 | Alkermes Pharma Ireland Limited | Thiophene prodrugs of naltroxene for long-acting injectable compositions and related methods |
| CA3149152A1 (en) | 2019-08-11 | 2021-02-18 | Kappa-Pharma LLC | Compositions and methods of enhancing opioid receptor engagement by opioid hexadienoates and optionally substituted hexadienoates |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0140367A2 (en) * | 1983-11-01 | 1985-05-08 | Ivax Laboratories, Inc. | Improved process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
-
1997
- 1997-07-04 CN CN97112842A patent/CN1050130C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0140367A2 (en) * | 1983-11-01 | 1985-05-08 | Ivax Laboratories, Inc. | Improved process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9969746B2 (en) | 2013-12-05 | 2018-05-15 | The University Of Bath | Opioid compounds and their uses |
| WO2022091131A1 (en) * | 2020-10-27 | 2022-05-05 | Navin Saxena Research & Technology Pvt. Ltd. | Process for preparation of pure naltrexone decanoate, its salts, composition and method of use thereof |
| EP4213849A4 (en) * | 2020-10-27 | 2024-10-30 | Navin Saxena Research & Tech Pvt Ltd | Process for preparation of pure naltrexone decanoate, its salts, composition and method of use thereof |
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|---|---|
| CN1204649A (en) | 1999-01-13 |
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